Selection for loss of p53 function in T-cell lymphomagenesis is alleviated by Moloney murine leukemia virus infection in myc transgenic mice

Baxter, E. W., Blyth, K. , Cameron, E. R. and Neil, J. C. (2001) Selection for loss of p53 function in T-cell lymphomagenesis is alleviated by Moloney murine leukemia virus infection in myc transgenic mice. Journal of Virology, 75(20), pp. 9790-9798. (doi: 10.1128/JVI.75.20.9790-9798.2001) (PMID:11559812) (PMCID:PMC114551)

Full text not currently available from Enlighten.


Thymic lymphomas induced by Moloney murine leukemia virus (MMLV) have provided many examples of oncogene activation, but the role of tumor suppressor pathways in these tumors is less clear. These tumors display little evidence of loss of heterozygosity, and MMLV is only weakly synergistic with the Trp53 null genotype, suggesting that viral lymphomagenesis involves mechanisms which do not require mutational loss of Trp53function. To explore this relationship in greater depth, we infected CD2-myc transgenic mice with MMLV and examined the role of Trp53 in the genesis of these tumors. Most (19 of 27) of the tumors from MMLV-infected, CD2-myc Trp53 +/− mice retained the wild-typeTrp53 allele in vivo while tumors of uninfected CD2-myc Trp53 +/− mice invariably showed allele loss from a significant fraction of primary tumor cells. The functional integrity of the Trp53gene in these tumors was indicated by ongoing allele loss or selection for mutational stabilization during in vitro propagation and by the radiosensitivity of selected Trp53 +/−tumor cell lines. An inverse correlation was noted between retention of the wild-type Trp53 allele and expression of p19ARF, providing further evidence of negative-feedback control of the latter by p53. However, expression of p19ARFdoes not appear to be counterselected in the absence of p53, and its integrity in Trp53 +/− tumors was indicated by its transcriptional upregulation on Trp53 wild-type allele loss in vitro in selected tumor cell lines. The role of MMLV was investigated further by analysis of proviral insertion sites in tumors of CD2-myc transgenic mice sorted forTrp53 genotype. A proportion of tumors showed insertions at Runx2, an oncogene which has been shown to collaborate independently with CD2-myc and with theTrp53 null genotype, and at a novel common integration site (ptl-1) on chromosome 8. Genotypic analysis of the panel of tumors suggested that neither of these integrations is functionally redundant with loss of p53, but it appears that the combination of the MMLV oncogenic program with the CD2-myc oncogene relegates p53 loss to a late step in tumor progression or in vitro culture. While the means by which these tumors preempt the p53 tumor suppressor response remains to be established, this study provides further evidence that irreversible inactivation of this pathway is not a prerequisite for tumor development in vivo.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Blyth, Professor Karen and Cameron, Professor Ewan and Neil, Professor James
Authors: Baxter, E. W., Blyth, K., Cameron, E. R., and Neil, J. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
Journal Name:Journal of Virology
Journal Abbr.:J. Virol.
Publisher:American Society for Microbiology
ISSN (Online):1098-5514

University Staff: Request a correction | Enlighten Editors: Update this record